Extrinsic factors, including personal life-styles, play a major role in the development of most human malignancies (Wynder, et al., J. Natl. Cancer Inst. 58:825-832 (1977); Higginson, et al., J. Natl. Cancer Inst. 63:1291-1298 (1979); Doll, et al., J. Natl. Cancer Inst. 63:1191-1308 (1981)). Cigarette smoking and consumption of alcohol, exposure to synthetic and naturally occurring carcinogens, radiation, drugs, infectious agents, and reproductive and behavioral practices are now widely recognized as important contributors to the etiology of cancer. But perhaps most surprising is the inference that normal human diets play causative roles in more than one-third (and possibly even two-thirds) of human neoplasia (Wynder, et al., J. Natl. Cancer Inst. 58:825-832 (1977); Higginson, et al., J. Natl. Cancer Inst. 63:1291-1298 (1979); Doll, et al., J. Natl. Cancer Inst. 63:1191-1308 (1981)). Our food contains not only numerous mutagens and carcinogens but also a variety of chemicals that block carcinogenesis in animal models (Ames, Science 221:1256-1264 (1983); Ames, et al. Proc. Natl. Acad. Sci. USA 87:7777-7781 (1990); Ames, et al., Proc. Natl. Acad. Sci. USA 87:7782-7786 (1990); Carr, B. I., Cancer 55:218-224 (1985); Fiala, et al., Annu. Rev. Nutr. 5:295-321 (1985); Wattenberg, Cancer Res. Suppl. 43:2448s- 2453s (1983); Wattenberg, Cancer Res. 45:1-8 (1985); Wattenberg, et al., Diet, Nutrition and Cancer: 193-203 (1986)). Furthermore, carcinogens can even protect against their own toxic and neoplastic effects or those of other carcinogens--i.e., carcinogens may act as anticarcinogens (Richardson, et al., Cancer Res. 11:274 (1951); Huggins, et al., J. Exp. Med. 119:923-942 (1964); Huggins, et al., J. Exp. Med. 119:943-954 (1964)).
Clearly, dietary modifications modulate cancer risk in various ways: for instance, through changes in caloric intake, by altering the consumption of nutritive and nonnutritive major components, and by providing exposure to numerous minor chemicals that may be genotoxic or protective (Ames, Science 221:1256-1264 (1983); Ames, et al., Proc. Natl. Acad. Sci. USA 87:7777-7781 (1990); Ames, et al., Proc. Natl. Acad. Sci. USA 87:7782-7786 (1990); Carr, Cancer 55:218-224 (1985); Wattenberg, Cancer Res. Suppl. 43:2448s-2453s (1983); Wattenberg, L. W., Cancer Res. 45:1-8 (1985); Wattenberg, et al., Diet, Nutrition and Cancer: 193-203 (1986); Tannenbaum, et al., Adv. Cancer Res. 1:451-501 (1953); National Research Council, Diet, Nutrition and Cancer, (1982); National Research Council, Diet and Health: Implications for Reducing Chronic Disease Risk, (1989); Creasey, Diet and Cancer, (1985); Knudsen, Genetic Toxicology of the Diet, (1986)). Rational recommendations for modifying human diets to reduce the risk of cancer require identification of dietary carcinogens and chemoprotectors, even though interactions among such factors in modulating cancer development are complex (Patterson, et al. Am. J. Public Health 78:282-286 (1988)). Whereas extensive efforts have been made to identify dietary carcinogens and mutagens (Ames, Science 221:1256-1264 (1983); Ames, et al. Proc. Natl. Acad. Sci. USA 87:7777-7781 (1990); Ames, et al., Proc. Natl. Acad. Sci. USA 87:7782-7786 (1990)), chemoprotective components have received far less attention.
Numerous epidemiological studies suggest that high consumption of yellow and green vegetables, especially those of the family Cruciferae (mustards) and the genus Brassica (cauliflower, cress, brussels sprouts, cabbage, broccoli), reduces the risk of developing cancer of various organs (Graham, et al., J. Natl. Cancer Inst. 61:709-714 (1978); Graham, Cancer Res. Suppl. 43:2409s-2413s (1983); Colditz, et al., Am. J. Clin. Nutr. 41:32-36 (1985); Kune, et al., Nutr. Cancer 9:21-42 (1987); La Vecchia, et al., J. Natl. Cancer Inst. 79:663-669 (1987); Le Marchand, et al., J. Natl. Cancer Inst. 81:1158-1164 (1989); You, et al., J. Natl. Cancer Inst. 81:162-164 (1989)). Moreover, administration of vegetables or of some of their chemical components to rodents also protects against chemical carcinogenesis (Wattenberg, Cancer Res. Suppl. 43:2448s-2453s (1983); Wattenberg, Cancer Res. 45:1-8 (1985); Wattenberg, et al., Diet, Nutrition and Cancer 193-203 (1986); Boyd, et al., Food Chem. Toxicol. 20:47-52 (1982)).
Well-documented evidence established that feeding of certain vegetables (e.g., brussels sprouts and cabbage) induces both phase I and phase II enzymes.sup.2 in animal tissues (Conney, et al., Fed. Proc. Fed. Am. Soc. Exp. Biol. 36:1647-1652 (1977); Sparnins, et al., J. Natl. Cancer Inst. 66:769-771 (1981); Sparnins, et al., J. Natl. Cancer Inst. 68:493-496 (1982); Aspry, et al., Food Chem. Toxicol. 21:133-142 (1983); Bradfield, et al., Food Chem. Toxicol. 23:899-904 (1985); Salbe, et al., Food Chem. Toxicol. 24:851-856 (1985); Whitty, et al., Food Chem. Toxicol. 25:581-587 (1987); Ansher, et al., Hepatology 3:932-935 (1983); Ansher, et al., Food Chem. Toxicol. 24:405-415 (1986)) and stimulates the metabolism of drugs in humans (Conney, et al., Fed. Proc. Fed. Am. Soc. Exp. Biol. 36:1647-1652 (1977); Pantuck, et al., Clin. Pharmacol. Ther. 25:88-95 (1979); Pantuck, et al., Clin. Pharmacol. Ther. 35:161-169 (1984)). The elevations of enzymes that metabolize xenobiotics may be highly relevant to the protective effects of vegetables, since relatively modest dietary changes not only affected the metabolism of drugs (Ansher, et al., Food Chem. Toxicol. 24:405-415 (1986)) but also modified the ability of carcinogens to cause tumors in rodents (Tannenbaum, et al., Adv. Cancer Res. 1:451-501 (1953); National Research Council, Diet, Nutrition and Cancer (1982); National Research Council, Diet and Health: Implications for Reducing Chronic Disease Risk (1989); Creasey, Diet and Cancer (1985); Knudsen, Genetic Toxicology of the Diet (1986); Longnecker, et al., Cancer 47:1562-1572 (1981); Fullerton, et al., Proc. Am. Assoc. Cancer Res. 29:147 (1988); Li, et al., Cancer Res. 50:3991-3996 (1990)). There is now very good evidence that when phase II enzymes are induced, animals and cells are protected against the toxic and neoplastic effects of carcinogens. In fact, anticarcinogens have been identified based on their ability to induce phase II enzymes. (Reviewed in Talalay (1992) "Chemical protection against cancer by induction of electrophile detoxication (phase II) enzymes" in Cellular and Molecular Targets of Chemoprevention, (V. E. Steele et al., eds.) CRC Press, Boca Raton, Fla.) FNT .sup.2 Enzymes of xenobiotic metabolism belong to two families (i) phase I enzymes (cytochromes P-450), which functionalize compounds, usually by oxidation or reduction; although their primary role is to detoxify xenobiotics, several cytochromes P-450 can activate procarcinogens to highly reactive ultimate carcinogens (Miller, et al., Bioactivation of Foreign Compounds, 3-28 (1985)); and (ii) phase II enzymes, which conjugate functionalized products with endogenous ligands (e.g., glutathione, flucuronic acid, sulfate) and serve primarily a detoxification role (Jakoby, et al., J. Biol. Chem. 265:20715-20718 (1990)). Quinone reductase (QR) is considered a phase II enzyme because it has protective functions (Prochaska, et al., Oxidative Stress: Oxidants and Antioxidants, 195-211 (1991)) is induced coordinately with other phase II enzymes, and is regulated by enhancer elements similar to those that control glutathione transferase (Favreau, et al., J. Biol. Chem. 266:4556-4561 (1991)).
There is a need in the art for the identification of specific compounds which are able to exert an anti-carcinogenic effect on mammals. Once identified, these chemoprotective compounds can be used as prophylactic medicaments or as food additives.